Hema­tol­ogy: How Far We’ve Come, Where We Go Next

At the 2021 Amer­i­can So­ci­ety of Hema­tol­ogy (ASH) An­nu­al Meet­ing & Ex­po­si­tion, blood can­cer re­searchers from around the world gath­ered vir­tu­al­ly to dis­cuss the progress that has been made in the field of hema­tol­ogy. Over the past decade, that progress has been tremen­dous. We’ve seen not on­ly break­through ap­proach­es to care, but al­so sig­nif­i­cant im­prove­ment up­on ex­ist­ing nov­el treat­ments and ex­plor­ing com­bi­na­tions with­in those med­i­cines.¹ These ad­vances have trans­formed ex­pec­ta­tions of what a blood can­cer di­ag­no­sis now means for pa­tients. While we’ve come a long way, I be­lieve the most ex­cit­ing sci­en­tif­ic dis­cov­ery is yet to come, and that fu­ture ad­vances will tru­ly trans­form pa­tient care.

Mov­ing be­yond tra­di­tion­al chemother­a­py

Look­ing ahead, we’ll con­tin­ue to see the con­ver­sa­tion in blood can­cer move be­yond tra­di­tion­al chemother­a­py to per­son­al­ized and tar­get­ed ther­a­pies, both as monother­a­py and in com­bi­na­tion.^2-5 Take, for in­stance, chron­ic lym­pho­cyt­ic leukemia (CLL), the most com­mon type of leukemia in adults.⁶ Al­though tra­di­tion­al chemother­a­py and chemoim­munother­a­py have pre­vi­ous­ly been the main­stay of ther­a­py for CLL, the ad­vent of tar­get­ed ther­a­py has im­proved clin­i­cal out­comes and is chang­ing clin­i­cal prac­tice.^2,4,7,8

Nov­el agents with new mech­a­nisms of ac­tion have en­abled ef­fec­tive and dif­fer­en­ti­at­ed tar­get­ing of can­cer cells, com­pared to tra­di­tion­al chemother­a­pies.^3,9-19 Such ad­vance­ments have, in turn, opened the pos­si­bil­i­ty of pro­long­ing pro­gres­sion-free sur­vival for pa­tients.^4,8

Our work with CALQUENCE^® (acal­abru­ti­nib), a next-gen­er­a­tion, se­lec­tive in­hibitor of Bru­ton ty­ro­sine ki­nase (BTK) is a good ex­am­ple of this.^20-22 We now have long-term fol­low-up da­ta from our CALQUENCE de­vel­op­ment pro­gram – through the EL­E­VATE-TN and AS­CEND Phase III stud­ies – with CALQUENCE ver­sus chemoim­munother­a­py agents in both the un­treat­ed and re­lapsed or re­frac­to­ry CLL set­tings.^23,24 At ASH 2021, we pre­sent­ed long-term fol­low-up da­ta from the AS­CEND Phase III tri­al, which looked at CALQUENCE at a me­di­an three years of fol­low-up in re­lapsed or re­frac­to­ry CLL when eval­u­at­ed ver­sus rit­ux­imab com­bined with the in­ves­ti­ga­tor’s choice of ide­lal­is­ib or ben­damus­tine, two chemoim­munother­a­py com­bi­na­tions.²³ These da­ta, com­bined with the long-term fol­low-up da­ta (me­di­an fol­low-up of ~4 years) from the EL­E­VATE-TN Phase III tri­al pre­sent­ed at AS­CO 2021, sug­gest CALQUENCE can be an ef­fec­tive front­line and re­lapsed or re­frac­to­ry treat­ment in CLL with an es­tab­lished, con­sis­tent safe­ty and tol­er­a­bil­i­ty pro­file.²³

While the clin­i­cal ben­e­fits of tar­get­ed ther­a­pies are well-es­tab­lished, tra­di­tion­al chemother­a­py is still of­ten used for most can­cer treat­ment.^25,26 That’s why As­traZeneca is al­so fo­cus­ing on ed­u­ca­tion that aims to in­crease the lev­el of un­der­stand­ing and aware­ness around the po­ten­tial ben­e­fits of tar­get­ed ther­a­pies in blood can­cer. We be­lieve by in­creas­ing aware­ness in med­ical com­mu­ni­ties among prac­tic­ing physi­cians and on­col­o­gists, as well as across the com­mu­ni­ty of in­di­vid­u­als af­fect­ed by it, we could ul­ti­mate­ly im­prove the lives of pa­tients and care­givers.

Pa­tient-guid­ed ap­proach­es

We rec­og­nize that dif­fer­ent pa­tients have dif­fer­ent needs.²⁷ For blood can­cer pa­tients, many fac­tors play an im­por­tant role in treat­ment se­lec­tion, in­clud­ing com­pli­ance, con­ve­nience, co­mor­bidi­ties, tox­i­c­i­ty and du­ra­tion of ther­a­py, among oth­ers.^28,29

In CLL specif­i­cal­ly, we know that tol­er­a­bil­i­ty is par­tic­u­lar­ly im­por­tant, as pa­tients tend to be old­er and may have oth­er co­mor­bidi­ties.^2,28,30-35 So, in ad­di­tion to liv­ing free from dis­ease pro­gres­sion, an ef­fec­tive op­tion that is al­so tol­er­a­ble be­comes cru­cial.^2,30-34 As we head in­to 2022, we’re ex­pect­ing even more safe­ty and tol­er­a­bil­i­ty da­ta from our Phase III AS­SURE tri­al with CALQUENCE in un­treat­ed and re­lapsed or re­frac­to­ry CLL, in­clud­ing those pre­vi­ous­ly on a BTK in­hibitor ther­a­py, which will fur­ther build on the knowl­edge we have gained from our es­tab­lished clin­i­cal tri­al pro­gram.³⁶

On top of this, we al­so must ac­knowl­edge the sig­nif­i­cant im­pact the COVID-19 pan­dem­ic has had on blood can­cer pa­tients over the past two years – more so than some oth­er com­mu­ni­ties.³⁷ We know that for peo­ple liv­ing with blood can­cers, there is a high­er risk of pro­longed in­fec­tion and death from COVID-19 be­cause pa­tients of­ten have ab­nor­mal or de­plet­ed lev­els of im­mune cells that pro­duce an­ti­bod­ies against virus­es.³⁷ Al­though vac­ci­na­tion is an im­por­tant mea­sure to help pre­vent COVID-19 in­fec­tions, ad­di­tion­al pre­cau­tions may al­so be nec­es­sary for in­di­vid­u­als who are ei­ther in­el­i­gi­ble for im­mu­niza­tion or who have co­mor­bidi­ties that could con­tribute to a re­duced im­mune re­sponse to a vac­cine.³⁷

Dur­ing this time, As­traZeneca has al­so been us­ing pa­tient in­sights in re­al time to adapt to a chang­ing health­care de­liv­ery in­fra­struc­ture and en­sure con­ti­nu­ity of care. For ex­am­ple, we have been ex­plor­ing oral­ly ad­min­is­tered ther­a­pies, which may of­fer more con­ve­nience and ease of ad­min­is­tra­tion.³⁸ To main­tain the pace and progress of our clin­i­cal tri­al pro­grams dur­ing COVID-19, we be­came more flex­i­ble and adapt­able, mak­ing it eas­i­er for pa­tients to par­tic­i­pate through tele­health, de­liv­er­ing med­ica­tions di­rect­ly to their homes, and fast-track­ing the im­ple­men­ta­tion of dig­i­tal tech­nolo­gies to close­ly mon­i­tor tri­als in re­al time.

A brighter fu­ture, to­geth­er

Fi­nal­ly, and per­haps most im­por­tant­ly, com­ing to­geth­er with med­ical col­leagues at ASH al­ways re­minds me that we can­not do this alone. While we will con­tin­ue to take bold ap­proach­es and push the bound­aries of sci­ence to trans­form pa­tient care in hema­tol­ogy, we rec­og­nize that out­smart­ing can­cer re­quires a col­lec­tive and col­lab­o­ra­tive ap­proach.

The fu­ture of hema­tol­ogy re­quires a deep com­mit­ment to part­ner­ing with pa­tients, health­care providers, pay­ers and pol­i­cy­mak­ers. By do­ing this, we can en­sure the best progress in the care of pa­tients with hema­to­log­ic ma­lig­nan­cies, tar­get­ing those blood can­cers with re­main­ing high un­met need and fo­cus­ing on mak­ing mean­ing­ful im­prove­ments in pa­tient out­comes.

For more in­for­ma­tion, vis­it www.calquence­hcp.com

IN­DI­CA­TION AND US­AGE

CALQUENCE is in­di­cat­ed for the treat­ment of adult pa­tients with chron­ic lym­pho­cyt­ic leukemia (CLL) or small lym­pho­cyt­ic lym­phoma (SLL).

IM­POR­TANT SAFE­TY IN­FOR­MA­TION ABOUT CALQUENCE® (acal­abru­ti­nib) cap­sules

Se­ri­ous and Op­por­tunis­tic In­fec­tions
Fa­tal and se­ri­ous in­fec­tions, in­clud­ing op­por­tunis­tic in­fec­tions, have oc­curred in pa­tients with hema­to­log­ic ma­lig­nan­cies treat­ed with CALQUENCE.

Se­ri­ous or Grade 3 or high­er in­fec­tions (bac­te­r­i­al, vi­ral, or fun­gal) oc­curred in 19% of 1029 pa­tients ex­posed to CALQUENCE in clin­i­cal tri­als, most of­ten due to res­pi­ra­to­ry tract in­fec­tions (11% of all pa­tients, in­clud­ing pneu­mo­nia in 6%). These in­fec­tions pre­dom­i­nant­ly oc­curred in the ab­sence of Grade 3 or 4 neu­trope­nia, with neu­tropenic in­fec­tion re­port­ed in 1.9% of all pa­tients. Op­por­tunis­tic in­fec­tions in re­cip­i­ents of CALQUENCE have in­clud­ed, but are not lim­it­ed to, he­pati­tis B virus re­ac­ti­va­tion, fun­gal pneu­mo­nia, Pneu­mo­cys­tis jirove­ci pneu­mo­nia, Ep­stein-Barr virus re­ac­ti­va­tion, cy­tomegalovirus, and pro­gres­sive mul­ti­fo­cal leukoen­cephalopa­thy (PML). Con­sid­er pro­phy­lax­is in pa­tients who are at in­creased risk for op­por­tunis­tic in­fec­tions. Mon­i­tor pa­tients for signs and symp­toms of in­fec­tion and treat prompt­ly.

He­m­or­rhage

Fa­tal and se­ri­ous he­m­or­rhag­ic events have oc­curred in pa­tients with hema­to­log­ic ma­lig­nan­cies treat­ed with CALQUENCE. Ma­jor he­m­or­rhage (se­ri­ous or Grade 3 or high­er bleed­ing or any cen­tral ner­vous sys­tem bleed­ing) oc­curred in 3.0% of pa­tients, with fa­tal he­m­or­rhage oc­cur­ring in 0.1% of 1029 pa­tients ex­posed to CALQUENCE in clin­i­cal tri­als. Bleed­ing events of any grade, ex­clud­ing bruis­ing and pe­techi­ae, oc­curred in 22% of pa­tients.

Use of an­tithrom­bot­ic agents con­comi­tant­ly with CALQUENCE may fur­ther in­crease the risk of he­m­or­rhage. In clin­i­cal tri­als, ma­jor he­m­or­rhage oc­curred in 2.7% of pa­tients tak­ing CALQUENCE with­out an­tithrom­bot­ic agents and 3.6% of pa­tients tak­ing CALQUENCE with an­tithrom­bot­ic agents. Con­sid­er the risks and ben­e­fits of an­tithrom­bot­ic agents when co-ad­min­is­tered with CALQUENCE. Mon­i­tor pa­tients for signs of bleed­ing.

Con­sid­er the ben­e­fit-risk of with­hold­ing CALQUENCE for 3-7 days pre- and post-surgery de­pend­ing up­on the type of surgery and the risk of bleed­ing.

Cy­tope­nias

Grade 3 or 4 cy­tope­nias, in­clud­ing neu­trope­nia (23%), ane­mia (8%), throm­bo­cy­tope­nia (7%), and lym­phope­nia (7%), de­vel­oped in pa­tients with hema­to­log­ic ma­lig­nan­cies treat­ed with CALQUENCE. Grade 4 neu­trope­nia de­vel­oped in 12% of pa­tients. Mon­i­tor com­plete blood counts reg­u­lar­ly dur­ing treat­ment. In­ter­rupt treat­ment, re­duce the dose, or dis­con­tin­ue treat­ment as war­rant­ed.

Sec­ond Pri­ma­ry Ma­lig­nan­cies

Sec­ond pri­ma­ry ma­lig­nan­cies, in­clud­ing skin can­cers and oth­er sol­id tu­mors, oc­curred in 12% of 1029 pa­tients ex­posed to CALQUENCE in clin­i­cal tri­als. The most fre­quent sec­ond pri­ma­ry ma­lig­nan­cy was skin can­cer, re­port­ed in 6% of pa­tients. Mon­i­tor pa­tients for skin can­cers and ad­vise pro­tec­tion from sun ex­po­sure.

Atri­al Fib­ril­la­tion and Flut­ter

Grade 3 atri­al fib­ril­la­tion or flut­ter oc­curred in 1.1% of 1029 pa­tients treat­ed with CALQUENCE, with all grades of atri­al fib­ril­la­tion or flut­ter re­port­ed in 4.1% of all pa­tients. The risk may be in­creased in pa­tients with car­diac risk fac­tors, hy­per­ten­sion, pre­vi­ous ar­rhyth­mias, and acute in­fec­tion. Mon­i­tor for symp­toms of ar­rhyth­mia (e.g., pal­pi­ta­tions, dizzi­ness, syn­cope, dys­p­nea) and man­age as ap­pro­pri­ate.

AD­VERSE RE­AC­TIONS

The most com­mon ad­verse re­ac­tions (≥ 30%) of any grade in pa­tients with CLL were ane­mia, * neu­trope­nia,* throm­bo­cy­tope­nia,* headache, up­per res­pi­ra­to­ry tract in­fec­tion, and di­ar­rhea.

*Treat­ment-emer­gent de­creas­es (all grades) of he­mo­glo­bin, platelets, and neu­trophils were based on lab­o­ra­to­ry mea­sure­ments and ad­verse re­ac­tions.

In pa­tients with pre­vi­ous­ly un­treat­ed CLL ex­posed to CALQUENCE, fa­tal ad­verse re­ac­tions that oc­curred in the ab­sence of dis­ease pro­gres­sion and with on­set with­in 30 days of the last study treat­ment were re­port­ed in 2% for each treat­ment arm, most of­ten from in­fec­tion. Se­ri­ous ad­verse re­ac­tions were re­port­ed in 39% of pa­tients in the CALQUENCE plus obin­u­tuzum­ab arm and 32% in the CALQUENCE monother­a­py arm, most of­ten due to events of pneu­mo­nia (7% and 2.8%, re­spec­tive­ly).

Ad­verse re­ac­tions led to CALQUENCE dose re­duc­tion in 7% and 4% of pa­tients in the CALQUENCE plus obin­u­tuzum­ab arm (N=178) and CALQUENCE monother­a­py arm (N=179), re­spec­tive­ly. Ad­verse events led to dis­con­tin­u­a­tion in 11% and 10% of pa­tients, re­spec­tive­ly. In­creas­es in cre­a­ti­nine 1.5 to 3 times the up­per lim­it of nor­mal oc­curred in 3.9% and 2.8% of pa­tients in the CALQUENCE com­bi­na­tion arm and monother­a­py arm, re­spec­tive­ly.

In pa­tients with re­lapsed/re­frac­to­ry CLL ex­posed to CALQUENCE, se­ri­ous ad­verse re­ac­tions oc­curred in 29% of pa­tients. Se­ri­ous ad­verse re­ac­tions in > 5% of pa­tients who re­ceived CALQUENCE in­clud­ed low­er res­pi­ra­to­ry tract in­fec­tion (6%). Fa­tal ad­verse re­ac­tions with­in 30 days of the last dose of CALQUENCE oc­curred in 2.6% of pa­tients, in­clud­ing from sec­ond pri­ma­ry ma­lig­nan­cies and in­fec­tion.

Ad­verse re­ac­tions led to CALQUENCE dose re­duc­tion in 3.9% of pa­tients (N=154), dose in­ter­rup­tions in 34% of pa­tients, most of­ten due to res­pi­ra­to­ry tract in­fec­tions fol­lowed by neu­trope­nia, and dis­con­tin­u­a­tion in 10% of pa­tients, most fre­quent­ly due to sec­ond pri­ma­ry ma­lig­nan­cies fol­lowed by in­fec­tion. In­creas­es in cre­a­ti­nine 1.5 to 3 times the up­per lim­it of nor­mal oc­curred in 1.3% of pa­tients who re­ceived CALQUENCE.

DRUG IN­TER­AC­TIONS

Strong CYP3A In­hibitors: Avoid co-ad­min­is­tra­tion with a strong CYP3A in­hibitor. If a strong CYP3A in­hibitor will be used short-term, in­ter­rupt CALQUENCE.

Mod­er­ate CYP3A In­hibitors: When CALQUENCE is co-ad­min­is­tered with a mod­er­ate CYP3A in­hibitor, re­duce CALQUENCE dose to 100 mg once dai­ly.

Strong CYP3A In­duc­ers: Avoid co-ad­min­is­tra­tion with a strong CYP3A in­duc­er. If a strong CYP3A in­duc­er can­not be avoid­ed, in­crease the CALQUENCE dose to 200 mg ap­prox­i­mate­ly every 12 hours.

Gas­tric Acid Re­duc­ing Agents: If treat­ment with a gas­tric acid re­duc­ing agent is re­quired, con­sid­er us­ing an H2-re­cep­tor an­tag­o­nist or an antacid. Take CALQUENCE 2 hours be­fore tak­ing an H2-re­cep­tor an­tag­o­nist. Sep­a­rate dos­ing with an antacid by at least 2 hours.

Avoid co-ad­min­is­tra­tion with pro­ton pump in­hibitors. Due to the long-last­ing ef­fect of pro­ton pump in­hibitors, sep­a­ra­tion of dos­es may not elim­i­nate the in­ter­ac­tion with CALQUENCE.

SPE­CIF­IC POP­U­LA­TIONS

Based on find­ings in an­i­mals, CALQUENCE may cause fe­tal harm and dys­to­cia when ad­min­is­tered to a preg­nant woman. There are no avail­able da­ta in preg­nant women to in­form the drug-as­so­ci­at­ed risk. Ad­vise preg­nant women of the po­ten­tial risk to a fe­tus.

Preg­nan­cy test­ing is rec­om­mend­ed for fe­males of re­pro­duc­tive po­ten­tial pri­or to ini­ti­at­ing CALQUENCE ther­a­py. Ad­vise fe­male pa­tients of re­pro­duc­tive po­ten­tial to use ef­fec­tive con­tra­cep­tion dur­ing treat­ment with CALQUENCE and for at least 1 week fol­low­ing the last dose of CALQUENCE.

It is not known if CALQUENCE is present in hu­man milk. Ad­vise lac­tat­ing women not to breast­feed while tak­ing CALQUENCE and for at least 2 weeks af­ter the fi­nal dose.

Avoid ad­min­is­tra­tion of CALQUENCE in pa­tients with se­vere he­pat­ic im­pair­ment. Dose mod­i­fi­ca­tions are not re­quired for pa­tients with mild or mod­er­ate he­pat­ic im­pair­ment.

Please see full Pre­scrib­ing In­for­ma­tion, in­clud­ing Pa­tient In­for­ma­tion.

Ref­er­ences

1. Smith J, Mil­nthor­pe J. Haema­to­log­i­cal ma­lig­nan­cies: a guide to nov­el ther­a­pies. Pre­scriber. 2020;31:9-15.
2. Pa­tel K, Pagel JM. Cur­rent and fu­ture treat­ment strate­gies in chron­ic lym­pho­cyt­ic leukemia. J Hema­tol On­col. 2021;14(1):69. doi:10.1186/s13045-021-01054-w.
3. Schef­fold A, Stil­gen­bauer S. Rev­o­lu­tion of chron­ic lym­pho­cyt­ic leukemia ther­a­py: the chemo-free treat­ment par­a­digm. Curr On­col Rep. 2020 Feb 5;22(2):16.
4. Shar­man JP, Egyed M, Ju­r­czak W, et al. Acal­abru­ti­nib with or with­out obin­u­tuzum­ab ver­sus chlo­ram­bu­cil and obin­u­tuzum­ab for treat­ment-naive chron­ic lym­pho­cyt­ic leukaemia (EL­E­VATE TN): a ran­domised, con­trolled, phase 3 tri­al [pub­lished cor­rec­tion ap­pears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2.
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6. Amer­i­can Can­cer So­ci­ety. What Is chron­ic lym­pho­cyt­ic leukemia. https://www.can­cer.org/can­cer/chron­ic-lym­pho­cyt­ic-leukemia/about/what-is-cll.html. Ac­cessed No­vem­ber 2021.
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16. Fur­man RR, Shar­man JP, Coutre SE, et al. Ide­lal­is­ib and rit­ux­imab in re­lapsed chron­ic lym­pho­cyt­ic leukemia. N En­gl J Med. 2014;370(11):997–1007.
17. Ze­lenetz AD, Bar­ri­en­tos JC, Brown JR, et al. Ide­lal­is­ib or place­bo in com­bi­na­tion with ben­damus­tine and rit­ux­imab in pa­tients with re­lapsed or re­frac­to­ry chron­ic lym­pho­cyt­ic leukaemia: in­ter­im re­sults from a phase 3, ran­domised, dou­ble-blind, place­bo-con­trolled tri­al. Lancet On­col. 2017 Mar;18(3):297-311. doi:10.1016/S1470-2045(16)30671-4.
18. Shar­man JP, Coutre SE, Fur­man RR, et al. Fi­nal re­sults of a ran­dom­ized, phase III study of rit­ux­imab with or with­out ide­lal­is­ib fol­lowed by open-la­bel ide­lal­is­ib in pa­tients with re­lapsed chron­ic lym­pho­cyt­ic leukemia. J Clin On­col. 2019 Jun 1;37(16):1391-1402.
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